Process for producing optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound

ABSTRACT

The present invention provides a production method of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), which includes a step of reacting glyoxylic acid compound (1-1) or (1-2) with aldehyde (2) in the presence of optically active pyrrolidine compound (3); 
                         
wherein each symbol is as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the U.S. national phase of International Patent Application No. PCT/JP2011/062317, filed on May 30, 2011, which claims the benefit of Japanese Patent Application No. 2010-125763, filed on Jun. 1, 2010, which are incorporated by reference in their entireties herein.

TECHNICAL FIELD

The present invention relates to a production method of an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound.

BACKGROUND ART

An optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound is known to be useful for, for example, as a drug substance or synthetic intermediate for a medicament, a pesticide and the like, or as a synthetic intermediate for vitamins such as pantothenic acid and the like.

Concerning production method of an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound, non-patent document 1 discloses a method of reacting ethyl glyoxylate monomer with hexanal in the presence of an axis asymmetry aminosulfonamide represented by the formula (10)

In addition, non-patent document 2 discloses a method of reacting ethyl glyoxylate polymer with isobutyraldehyde in the presence of optically active histidine.

DOCUMENT LIST Non-Patent Document

-   Non-Patent Document 1: Angew. Chem. Int. Ed. 2007, 46, 1738 -   Non-Patent Document 2: J. Am. Chem. Soc. 2009, 131, 16642

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

An object of the present invention is to provide a new method capable of producing an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound.

Generally, glyoxylic acid compound is commercially available in the form of a toluene solution of a polymer. Monomers are advantageous in that they have higher reactivity than polymers. While a monomer is produced by thermal decomposition of a polymer, since it has high reactivity, it easily polymerizes or immediately reacts with water. Thus, use in the form of a monomer is associated with problems of the need for thermal decomposition of the polymer, followed by distillation immediately before use, limitation to non-aqueous reactions, and the like. Therefore, use in the form of a polymer has been desired.

Means of Solving the Problems

Under the circumstances, the present inventors have studied a new production method of an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound wherein a glyoxylic acid compound can be used in the form of a polymer, and found that a reaction in the presence of a particular asymmetric catalyst is superior in the production of an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound, which resulted in the completion of the present invention. Accordingly, the present invention is as follows.

-   [1] A method of producing an optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound represented     by the formula (4):

wherein

-   R¹ is a C₁-C₂₀ hydrocarbon group optionally having substituent(s)     selected from the following Group G1 or a hydrogen atom, -   R² and R³ are each independently a C₁-C₂₀ hydrocarbon group     optionally having substituent(s) selected from the following Group     G1, a C₁-C₁₂ alkoxy group optionally having substituent(s) selected     from the following Group G1, a heterocyclic group optionally having     substituent(s) selected from the following Group G1 or a hydrogen     atom, and -   the carbon atom marked with * is an asymmetric carbon atom,     (hereinafter referred to as optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4)), which     comprises a step of reacting a glyoxylic acid compound represented     by the formula (1-1):

-   wherein R¹ is as defined above, and n is an integer of 2 or more     (hereinafter referred to as glyoxylic acid compound (1-1)), or a     glyoxylic acid compound represented by the formula (1-2):

-   wherein R¹ and n are as defined above (hereinafter referred to as     glyoxylic acid compound (1-2)) with an aldehyde represented by the     formula (2):

-   wherein R² and R³ are as defined above (hereinafter referred to as     aldehyde (2)) in the presence of an optically active pyrrolidine     compound represented by the formula (3):

wherein

-   Ar¹ and Ar² are each independently a phenyl group optionally having     substituent(s) selected from the following Group G2, a C₁-C₁₂ chain     hydrocarbon group, a C₃-C₁₂ alicyclic hydrocarbon group or a     hydrogen atom, -   R⁴ is a hydrogen atom, a fluorine atom, a hydroxyl group, a C₁-C₁₂     alkoxy group, a C₁-C₁₂ fluorinated alkyloxy group or a silyloxy     group represented by —OSiR⁵R⁶R⁷ wherein R⁵, R⁶ and R⁷ are each     independently a C₁-C₈ alkyl group or a C₆-C₂₀ aryl group, and -   the carbon atom marked with ** is an asymmetric carbon atom,     (hereinafter referred to as optically active pyrrolidine compound     (3)); -   Group G1: the group consisting of a C₆-C₂₀ aryl group optionally     having substituent(s) selected from Group G2, an aromatic     heterocyclic group optionally having substituent(s) selected from     Group G2, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ alkoxy group having C₆-C₂₀     aryl group(s) optionally having substituent(s) selected from Group     G2, a halogen atom and an oxo group; -   Group G2: the group consisting of a C₁-C₁₂ alkyl group, a C₁-C₁₂     alkoxy group, a C₂-C₁₃ alkoxycarbonyl group, a C₁-C₁₂ fluorinated     alkyl group, a C₂-C₁₃ acyl group, a nitro group, a cyano group, a     protected amino group and a halogen atom. -   [2] The method of the above-mentioned [1], wherein the reaction is     carried out in the presence of a solvent. -   [3] The method of the above-mentioned [2], wherein the solvent is at     least one selected from the group consisting of an aromatic     hydrocarbon solvent, an alcohol solvent, a halogenated hydrocarbon     solvent, an ether solvent, a nitrile solvent and water. -   [4] The method of the above-mentioned [1], wherein the reaction is     carried out within the range of 0-50° C. -   [5] The method of the above-mentioned [1], wherein R³ is a hydrogen     atom. -   [6] The method of the above-mentioned [1], wherein R⁴ is a hydroxyl     group, and Ar¹ and Ar² are each independently a phenyl group     optionally having C₁-C₁₂ fluorinated alkyl group(s). -   [7] The method of the above-mentioned [1], wherein R⁴ is a hydroxyl     group, and Ar¹ and Ar² are both 3,5-bis(trifluoromethyl)phenyl     groups. -   [8] The method of the above-mentioned [6] or [7], wherein the     absolute configuration of C** is S-configuration, and the absolute     configuration of C* is R-configuration. -   [9] A method of producing an optically active acetal compound     represented by the formula (5):

wherein

-   R¹, R² and R³ are as defined in the above-mentioned [1], -   R⁸ is a C₁-C₈ alkyl group, and -   the carbon atom marked with * is an asymmetric carbon atom     (hereinafter referred to as optically active acetal compound (5)),     which comprises a step of reacting optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), which     is obtained according to the method of any of the above-mentioned     [1] to [8], with R⁸OH or HC(OR⁸)₃ wherein R⁸ is as defined above, in     the presence of an acid catalyst. -   [10] A method of producing an optically active α,β-unsaturated ester     compound represented by the formula (6):

wherein

-   R¹, R² and R³ are as defined in the above-mentioned [1], -   R⁹ is a C₁-C₈ alkyl group, and -   the carbon atom marked with * is an asymmetric carbon atom     (hereinafter referred to as optically active α,β-unsaturated ester     compound (6)), which comprises a step of reacting optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), which     is obtained according to the method of any of the above-mentioned     [1] to [8], with Ph₃P═CHCO₂R⁹ wherein Ph is a phenyl group, and R⁹     is as defined above.

Effect of the Invention

According to the production method of the present invention, since the reactivity of the reaction in the presence of optically active pyrrolidine compound (3) as a catalyst is superior even when glyoxylic acid compound (1-1) or (1-2) is used in the form of a polymer, a commercially available product can be used, and a complicated step such as thermal decomposition and distillation immediately before use is not necessary. In addition, reaction under aqueous conditions is also possible. Furthermore, when reacted in toluene, a commercially available product can be advantageously used directly without evaporating toluene.

Using optically active pyrrolidine compound (3) having a particular structure and a particular solvent, an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) can be produced in a high yield with superior enantioselectivity and diastereoselectivity (when R² and R³ in aldehyde (2) are different groups).

DESCRIPTION OF EMBODIMENTS

The present invention is explained in detail below.

In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C₁-C₂₀ hydrocarbon group” means a C₁-C₂₀ aliphatic hydrocarbon group or a C₆-C₂₀ aromatic hydrocarbon group.

In the present specification, the “C₁-C₂₀) aliphatic hydrocarbon group” means a C₁-C₂₀ chain hydrocarbon group or a C₃-C₂₀ alicyclic hydrocarbon group.

In the present specification, the “C₁-C₁₂ aliphatic hydrocarbon group” means a C₁-C₁₂ chain hydrocarbon group or a C₃-C₁₂ alicyclic hydrocarbon group.

In the present specification, the “C₁-C₂₀ chain hydrocarbon group” means a C₁-C₂₀ alkyl group, a C₂-C₂₀ alkenyl group or a C₂-C₂₀ alkynyl group.

In the present specification, the “C₁-C₁₂ chain hydrocarbon group” means a C₁-C₁₂ alkyl group, a C₂-C₁₂ alkenyl group or a C₂-C₁₂ alkynyl group.

In the present specification, the “C₁-C₂₀ alkyl group” means a straight or branched chain alkyl group having 1 to 20 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl and the like. Among them, a C₁-C₁₂ alkyl group is preferable, and a C₁-C₈ alkyl group is particularly preferable.

In the present specification, the “C₁-C₁₂ alkyl group” means a straight or branched chain alkyl group having 1 to 12 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Among them, a C₁-C₈ alkyl group is preferable, and a C₁-C₄ alkyl group is particularly preferable.

In the present specification, the “C₁-C₈ alkyl group” means a straight or branched chain alkyl group having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl and the like. Among them, a C₁-C₄ alkyl group is preferable.

In the present specification, the “C₁₋₆ alkyl (group)” means a straight or branched chain alkyl (group) having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Among them, a C₁-C₄ alkyl (group) is preferable.

In the present specification, the “C₁₋₄ alkyl (group)” means a straight or branched chain alkyl (group) having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

In the present specification, the “C₂-C₂₀ alkenyl group” means a straight or branched chain alkenyl group having 2 to 20 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, 1-tridecenyl, 1-eicosenyl and the like. Among them, a C₂-C₁₂ alkenyl group is preferable, and a C₂-C₈ alkenyl group is particularly preferable.

In the present specification, the “C₂-C₁₂ alkenyl group” means a straight or branched chain alkenyl group having 2 to 12 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl and the like. Among them, a C₂-C₈ alkenyl group is preferable, and a C₂-C₄ alkenyl group is particularly preferable.

In the present specification, the “C₂-C₆ alkenyl (group)” means a straight or branched chain alkenyl (group) having 2 to 6 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like. Among them, a C₂-C₄ alkenyl (group) is particularly preferable.

In the present specification, the “C₂-C₂₀ alkynyl group” means a straight or branched chain alkynyl group having 2 to 20 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl, 1-tridecynyl, 1-eicosynyl and the like. Among them, a C₂-C₁₂ alkynyl group is preferable, and a C₂-C₈ alkynyl group is particularly preferable.

In the present specification, the “C₂-C₁₂ alkynyl group” means a straight or branched chain alkynyl group having 2 to 12 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl and the like. Among them, a C₂-C₈ alkynyl group is preferable, and a C₂-C₄ alkynyl group is particularly preferable.

In the present specification, the “C₃-C₂₀ alicyclic hydrocarbon group” means a C₃-C₂₀ cycloalkyl group or a C₄-C₂₀ cycloalkenyl group.

In the present specification, the “C₃-C₁₂ alicyclic hydrocarbon group” means a C₃-C₁₂ cycloalkyl group or a C₄-C₁₂ cycloalkenyl group.

In the present specification, the “C₃-C₂₀ cycloalkyl group” means a cyclic alkyl group having 3 to 20 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cycloeicosyl and the like. Among them, a C₃-C₁₂ cycloalkyl group is preferable, and a C₃-C₈ cycloalkyl group is particularly preferable.

In the present specification, the “C₃-C₁₂ cycloalkyl group” means a cyclic alkyl group having 3 to 12 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. Among them, a C₃-C₈ cycloalkyl group is preferable.

In the present specification, the “C₄-C₂₀ cycloalkenyl group” means a cyclic alkenyl group having 4 to 20 carbon atoms, and examples thereof include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecen-1-yl, 2-cyclododecen-1-yl, 2-cycloeicosen-1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Among them, a C₄-C₁₂ cycloalkenyl group is preferable, and a C₄-C₈ cycloalkenyl group is particularly preferable.

In the present specification, the “C₄-C₁₂ cycloalkenyl group” means a cyclic alkenyl group having 4 to 12 carbon atoms, and examples thereof include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecen-1-yl, 2-cyclododecen-1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Among them, a C₄-C₈ cycloalkenyl group is preferable.

In the present specification, the “C₃-C₂₀ cycloalkyl group”, “C₃-C₁₂ cycloalkyl group”, “C₄-C₂₀ cycloalkenyl group” and “C₄-C₁₂ cycloalkenyl group” are optionally fused with a benzene ring, and examples thereof include 1,2-dihydronaphthalen-1-yl, 1,2-dihydronaphthalen-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, fluoren-9-yl, inden-1-yl and the like.

In the present specification, the “C₆-C₂₀ aromatic hydrocarbon group (the C₆-C₂₀ aryl group)” means a monocyclic or polycyclic (fused) hydrocarbon group having 6 to 20 carbon atoms and showing aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl, acenaphthyl, naphthacenyl, biphenylyl and the like. Among them, a C₆-C₁₄ aromatic hydrocarbon group (a C₆-C₁₄ aryl group) is preferable, and a C₆-C₁₀ aromatic hydrocarbon group (a C₆-C₁₀ aryl group) is particularly preferable.

In the present specification, the “C₆-C₁₂ aromatic hydrocarbon group (the C₆-C₁₂ aryl group)” means a monocyclic or polycyclic (fused) hydrocarbon group having 6 to 12 carbon atoms and showing aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, acenaphthyl, biphenylyl and the like. Among them, a C₆-C₁₀ aromatic hydrocarbon group (a C₆-C₁₀ aryl group) is preferable.

In the present specification, the “C₆-C₁₀ aryl (group)” means a monocyclic or polycyclic (fused) hydrocarbon group having 6 to 10 carbon atoms and showing aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like.

In the present specification, the “C₇-C₁₄ aralkyl (group)” means a “C₁₋₄ alkyl (group)” substituted by “C₆-C₁₀ aryl (group(s))”, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, (1-naphthyl)methyl, (2-naphthyl)methyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl and the like.

In the present specification, the “C₁-C₁₂ alkoxy group” means a straight or branched chain alkoxy group having 1 to 12 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy and the like. Among them, a C₁-C₈ alkoxy group is preferable, and a C₁-C₄ alkoxy group is particularly preferable.

In the present specification, the “C₁-C₆ alkoxy (group)” means a straight or branched chain alkoxy (group) having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Among them, a C₁-C₄ alkoxy (group) is preferable.

In the present specification, the “heterocyclic group” means an aromatic heterocyclic group or a non-aromatic heterocyclic group.

In the present specification, the “aromatic heterocyclic group” means a monocyclic or polycyclic (fused) heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and showing aromaticity.

In the present specification, examples of the “monocyclic aromatic heterocyclic group” include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (1,2,4-triazolyl, 1,2,3-triazolyl), tetrazolyl, triazinyl and the like. Among them, a 5- or 6-membered monocyclic aromatic heterocyclic group is preferable.

In the present specification, the “fused aromatic heterocyclic group” means the above-mentioned monocyclic aromatic heterocyclic group fused with a monocyclic aromatic ring (preferably a benzene ring or a monocyclic aromatic heterocycle), and examples thereof include quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, thienopyridyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, thienopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, thienopyrimidinyl, pyrazolothienyl and the like.

In the present specification, examples of the “monocyclic aromatic heterocycle” include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (1,2,4-oxadiazole, 1,3,4-oxadiazole), thiadiazole (1,2,4-thiadiazole, 1,3,4-thiadiazole), triazole (1,2,4-triazole, 1,2,3-triazole), tetrazole, triazine and the like. Among them, a 5- or 6-membered monocyclic aromatic heterocycle is preferable.

In the present specification, the “non-aromatic heterocyclic group” means a monocyclic or fused heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and not showing aromaticity.

Examples of the “monocyclic non-aromatic heterocyclic group” include aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, azepanyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, imidazolinyl, pyrazolidinyl, dioxolyl, dioxolanyl, dihydrooxadiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, dihydropyridyl, tetrahydropyridyl, tetrahydropyrimidinyl and the like.

In the present specification, the “fused non-aromatic heterocyclic group” means the above-mentioned monocyclic non-aromatic heterocyclic group fused with a monocyclic aromatic ring (preferably a benzene ring or a monocyclic aromatic heterocycle), or a fully or partially-saturated group thereof, and examples thereof include dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, tetrahydrobenzofuranyl, dihydrobenzodioxinyl, dihydrobenzodioxepinyl, chromenyl, dihydrochromenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydrophthalazinyl, azabicyclohexyl and the like.

In the present specification, the “C₁-C₁₂ fluorinated alkyl (group)” means a “C₁₋₁₂ alkyl (group)” substituted by fluorine atom(s). The number of the fluorine atoms is not particularly limited, and the C₁-C₁₂ fluorinated alkyl (group) may be perfluoro-substituted. Specific examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, 10-fluorodecyl, 11-fluoroundecyl, 12-fluorododecyl and the like.

In the present specification, the “C₁-C₁₂ fluorinated alkyloxy group” means a “C₁₋₁₂ alkoxy group” substituted by fluorine atom(s). The number of the fluorine atoms is not particularly limited, and the C₁-C₁₂ fluorinated alkyloxy group may be perfluoro-substituted. Specific examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy, 7-fluoroheptyloxy, 8-fluorooctyloxy, 9-fluorononyloxy, 10-fluorodecyloxy, 11-fluoroundecyloxy, 12-fluorododecyloxy and the like.

In the present specification, the “C₂-C₁₃ alkoxycarbonyl group” means a group wherein a “C₁-C₁₂ alkoxy group” is bonded to —C═O—, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl and the like. Among them, a C₂-C₉ alkoxycarbonyl group is preferable, and a C₂-C₅ alkoxycarbonyl group is particularly preferable.

In the present specification, the “C₂-C₁₃ acyl group” is a residue obtained by removing a hydroxyl group from a C₂-C₁₃ carboxylic acid, and it means a “C₂-C₁₃ aliphatic acyl group” or a “C₇-C₁₃ aromatic acyl group”.

In the present specification, the “C₂-C₁₃ aliphatic acyl group” means a group wherein a “C₁-C₁₂ aliphatic hydrocarbon group” is bonded to —C═O—, and examples thereof include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, propionoyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like. Among them, a C₂-C₁₃ alkylcarbonyl group is preferable, and a C₂-C₉ alkylcarbonyl group is particularly preferable.

In the present specification, the “C₇-C₁₃ aromatic acyl group” means a group wherein a “C₆-C₁₂ aromatic hydrocarbon group (a C₆-C₁₂ aryl group)” is bonded to —C═O—, and examples thereof include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

In the present specification, the “protected amino group” means an amino group protected by a “protecting group”. Examples of the “protecting group” include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₆₋₁₀ aryl group, a C₇₋₁₄ aralkyl group, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₂₋₆ alkenyl-oxycarbonyl group, a C₆₋₁₀ aryl-carbonyl group, a C₇₋₁₄ aralkyl-carbonyl group, a C₆₋₁₀ aryl-oxycarbonyl group, a C₇₋₁₄ aralkyl-oxycarbonyl group, a C₆₋₁₀ arylsulfonyl group, a benzhydryl group, a trityl group, a tri-C₁₋₆ alkylsilyl group, a 9-fluorenylmethyloxycarbonyl group, a phthaloyl group and the like. The above-mentioned protecting group is optionally substituted by a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group or a nitro group.

Specific examples of the protecting group include acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzhydryl, trityl, phthaloyl, allyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and the like.

Each group of the formulas (1-1), (1-2) and (2)-(6) is explained below.

R¹ is a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from Group G1 or a hydrogen atom. The number of the substituents for the C₁-C₂₀ hydrocarbon group is preferably 1 to 3. When it is 2 or more, these substituents may be the same or different.

R¹ is

-   preferably a C₁-C₂₀ hydrocarbon group optionally having     substituent(s) selected from Group G1, -   more preferably a C₁-C₂₀ alkyl group optionally having     substituent(s) selected from Group G1, -   further more preferably a C₁-C₁₂ alkyl group optionally having     substituent(s) selected from Group G1, -   still more preferably a C₁-C₈ alkyl group optionally having     substituent(s) selected from Group G1, -   particularly preferably a C₁-C₄ alkyl group (particularly ethyl     group).

n is an integer of 2 or more.

n is preferably an integer of 3 to 100000.

R² and R³ are each independently a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from Group G1, a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from Group G1, a heterocyclic group optionally having substituent(s) selected from Group G1 or a hydrogen atom. The number of the substituents for the C₁-C₂₀ hydrocarbon group, C₁-C₁₂ alkoxy group and heterocyclic group is preferably 1 to 3. When it is 2 or more, these substituents may be the same or different.

R² is

-   preferably a C₁-C₂₀ alkyl group optionally having substituent(s)     selected from Group G1, a C₁-C₁₂ alkoxy group optionally having     substituent(s) selected from Group G1, a heterocyclic group     optionally having substituent(s) selected from Group G1 or a     hydrogen atom, -   more preferably a C₁-C₁₂ alkyl group optionally having     substituent(s) selected from Group G1, a C₁-C₈ alkoxy group     optionally having substituent(s) selected from Group G1, a     non-aromatic heterocyclic group optionally having substituent(s)     selected from Group G1 or a hydrogen atom, further more preferably a     C₁-C₈ alkyl group optionally having substituent(s) selected from     Group G1, a C₁-C₄ alkoxy group optionally having substituent(s)     selected from Group G1, a non-aromatic heterocyclic group optionally     having substituent(s) selected from Group G1 or a hydrogen atom,     still more preferably a C₁-C₄ alkyl group optionally having     substituent(s) selected from Group G1, a C₁-C₄ alkoxy group     optionally having substituent(s) selected from Group G1, a     non-aromatic heterocyclic group optionally having substituent(s)     selected from Group G1 or a hydrogen atom, particularly preferably -   (1) a hydrogen atom, -   (2) a C₁-C₄ alkyl group optionally having substituent(s) selected     from     -   (i) a C₆-C₂₀ aryl group (preferably a C₆-C₁₀ aryl group,         particularly preferably a phenyl group), and     -   (ii) a C₁-C₁₂ alkoxy group (preferably a C₁-C₈ alkoxy group,         particularly preferably a C₁-C₄ alkoxy group) having C₆-C₂₀ aryl         group(s) (preferably C₆-C₁₀ aryl group(s), particularly         preferably phenyl group(s)) optionally having C₁-C₁₂ alkoxy         group(s) (preferably C₁-C₈ alkoxy group(s), particularly         preferably C₁-C₄ alkoxy group(s)), -   (3) a C₁-C₄ alkoxy group optionally having C₆-C₂₀ aryl group(s)     (preferably C₆-C₁₀ aryl group(s), particularly preferably phenyl),     or -   (4) an N-containing non-aromatic heterocyclic group (preferably     isoindolyl) optionally having oxo group(s).

Specific preferable examples of R² include a hydrogen atom, methyl, ethyl, propyl, isopropyl, benzyl, benzyloxy, p-methoxybenzyloxymethyl, 1,3-dioxoisoindolyl and the like.

R³ is preferably a hydrogen atom.

Ar¹ and Ar² are each independently a phenyl group optionally having substituent(s) selected from Group G2, a C₁-C₁₂ chain hydrocarbon group, a C₃-C₃₂ alicyclic hydrocarbon group or a hydrogen atom. The number of the substituents for the phenyl group is preferably 1 to 3. When it is 2 or more, these substituents may be the same or different.

Ar¹ and Ar² are

-   preferably each independently a phenyl group optionally having     substituent(s) selected from Group G2, -   more preferably each independently a phenyl group optionally having     C₁-C₁₂ fluorinated alkyl group(s), -   further more preferably each independently a phenyl group optionally     having C₁-C₄ fluorinated alkyl group(s), -   still more preferably each independently a phenyl group optionally     having trifluoromethyl group(s), -   still more preferably both phenyl groups or both     3,5-bis(trifluoromethyl)phenyl groups, -   particularly preferably both 3,5-bis(trifluoromethyl)phenyl groups.

R⁴ is a hydrogen atom, a fluorine atom, a hydroxyl group, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ fluorinated alkyloxy group or a silyloxy group represented by —OSiR⁵R⁶R⁷ wherein R⁵, R⁶ and R⁷ are each independently a C₁-C₈ alkyl group or a C₆-C₂₀ aryl group.

R⁴ is

-   preferably a hydroxyl group or a silyloxy group represented by     —OSiR⁵R⁶R⁷ wherein R⁵, R⁶ and R⁷ are as defined above, more     preferably a hydroxyl group, or a silyloxy group represented by     —OSiR⁵R⁶R⁷ wherein R⁵, R⁶ and R⁷ are each independently a C₁-C₈     alkyl group (preferably a methyl group), particularly preferably a     hydroxyl group.

Preferable combination of Ar¹, Ar² and R⁴ is as follows:

-   (1) An embodiment wherein Ar¹ and Ar² are each independently a     phenyl group optionally having substituent(s) selected from Group     G2, and R⁴ is a hydroxyl group. -   (2) An embodiment wherein Ar¹ and Ar² are each independently a     phenyl group optionally having C₁-C₁₂ fluorinated alkyl group(s),     and R⁴ is a hydroxyl group. -   (3) An embodiment wherein Ar¹ and Ar² are each independently a     phenyl group optionally having C₁-C₄ fluorinated alkyl group(s), and     R⁴ is a hydroxyl group. -   (4) An embodiment wherein Ar¹ and Ar² are each independently a     phenyl group optionally having trifluoromethyl group(s), and R⁴ is a     hydroxyl group. -   (5) An embodiment wherein Ar¹ and Ar² are both phenyl groups or both     3,5-bis(trifluoromethyl)phenyl groups, and R⁴ is a hydroxyl group. -   (6) An embodiment wherein Ar¹ and Ar² are both     3,5-bis(trifluoromethyl)phenyl groups, and R⁴ is a hydroxyl group.

R⁸ is a C₁-C₈ alkyl group.

R⁸ is preferably a C₁-C₄ alkyl group (particularly methyl).

R⁹ is a C₁-C₈ alkyl group.

R⁹ is preferably a C₁-C₄ alkyl group (particularly ethyl, tert-butyl).

In the present invention, optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) is produced by a step of reacting glyoxylic acid compound (1-1) or (1-2) with aldehyde (2) in the presence of optically active pyrrolidine compound (3) as a catalyst (aldol reaction step).

Glyoxylic acid compound (1-1) or (1-2) is a polymer of the glyoxylic acid compound represented by the formula (1′):

wherein R¹ are as defined above. Generally, glyoxylic acid compound is commercially available in the form of a toluene solution of a polymer (i.e., glyoxylic acid compound (1-1) or (1-2)). Monomers are advantageous in that they have higher reactivity than polymers. While a monomer (i.e., glyoxylic acid compound (1′)) is produced by thermal decomposition of a polymer, since it has high reactivity, it easily polymerizes or immediately reacts with water. Thus, use in the form of a monomer is associated with problems of the need for thermal decomposition of the polymer, followed by distillation immediately before use, limitation to non-aqueous reactions, and the like.

The reactivity is superior in the aldol reaction step in the present invention even by use in the form of a polymer. Therefore, a commercially available product can be used, and a complicated step such as thermal decomposition and distillation immediately before use is not necessary. In addition, reaction under aqueous conditions is also possible. Furthermore, when reacted in toluene, a commercially available product can be advantageously used directly without evaporating toluene.

The amount of aldehyde (2) to be used is preferably 0.5-10 mol, more preferably 0.5-5 mol, per 1 mol of glyoxylic acid compound (1-1) or (1-2) (in monomer amount), in view of yield, selectivity and economic efficiency.

The catalyst, optically active pyrrolidine compound (3) is preferably an optically active pyrrolidine compound represented by the formula (3a):

wherein

-   Ar¹ and Ar² are as defined above, and -   the carbon atom marked with ** is an asymmetric carbon atom, in view     of diastereoselectivity (when R² and R³ of aldehyde (2) are     different groups), though depending on the kind of aldehyde (2).     Among them, an optically active pyrrolidine compound wherein Ar¹ and     Ar² are each independently a phenyl group optionally having C₁-C₄     fluorinated alkyl group(s) is preferable, -   an optically active pyrrolidine compound wherein Ar¹ and Ar² are     each independently a phenyl group optionally having trifluoromethyl     group(s) is more preferable, -   an optically active pyrrolidine compound wherein Ar¹ and Ar² are     both phenyl groups or both 3,5-bis(trifluoromethyl)phenyl groups is     still more preferable, and -   an optically active pyrrolidine compound wherein Ar¹ and Ar² are     both 3,5-bis(trifluoromethyl)phenyl groups is particularly     preferable.

The amount of optically active pyrrolidine compound (3) to be used is preferably 0.5-30 mol %, more preferably 1-20 mol %, particularly preferably 5-15 mol %, relative to glyoxylic acid compound (1-1) or (1-2) (in monomer amount), in view of yield and economic efficiency.

The aldol reaction step of the present invention is preferably carried out in the presence of a solvent. Examples of the solvent to be used in the present invention include an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); an alcohol solvent (e.g., methanol, ethanol); a halogenated hydrocarbon solvent (e.g., chloroform, dichloromethane, carbon tetrachloride); an ether solvent (e.g., diethyl ether, tetrahydrofuran); a nitrile solvent (e.g., acetonitrile); an aprotic polar solvent (e.g., dimethylformamide, dimethylacetamide); water; a mixed solvent thereof and the like.

An aromatic hydrocarbon solvent; an alcohol solvent; a halogenated hydrocarbon solvent; an ether solvent; a nitrile solvent; water; a mixed solvent thereof and the like are preferable from among them in view of enantioselectivity and diastereoselectivity (when R² and R³ of aldehyde (2) are different groups), and a mixed solvent of nitrile solvent and water is particularly preferable in view of superior enantioselectivity and diastereoselectivity, though depending on the kind of aldehyde (2). When the solvent is a mixed solvent of nitrile solvent and water, the amount of water to be used is preferably 1-5 mol, more preferably 2-4 mol, per 1 mol of the nitrile solvent.

The amount of the solvent to be used is preferably 0.2-20 mL per 1 g of aldehyde compound (2).

When the aldol reaction is carried out in a solvent free of toluene, glyoxylic acid compound (1-1) or (1-2) after concentrating the commercially available toluene solution is used.

The aldol reaction step of the present invention is carried out by a method of adding aldehyde (2), optically active pyrrolidine compound (3) and solvent to glyoxylic acid compound (1-1) or (1-2), and then mixing them; a method of mixing glyoxylic acid compound (1-1) or (1-2), optically active pyrrolidine compound (3) and solvent, and then adding aldehyde (2) thereto; and the like. In view of yield and selectivity, the step is preferably carried out by a method of adding aldehyde (2), optically active pyrrolidine compound (3) and solvent to glyoxylic acid compound (1-1) or (1-2), and then mixing them.

The aldol reaction step in the present invention is carried out preferably within the range of 0-50° C., more preferably within the range of 0-40° C., though depending on the kind of aldehyde (2).

While the reaction time varies depending on the kind of aldehyde (2) and the reaction temperature, it is preferably 1-100 hr, more preferably 10-50 hr, particularly preferably 20-40 hr.

The progress of the reaction can be confirmed by an analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

Optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) contained in thus obtained reaction mixture can be isolated by subjecting the reaction mixture to a post-treatment using a conventional method (e.g., neutralization, extraction, washing with water, distillation, crystallization etc.), and purified by subjecting optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment using activated carbon, silica, alumina and the like, or chromatography treatment using silica gel column chromatography and the like.

When R² and R³ in aldehyde (2) are different groups, diastereomers (syn-form and anti-form) exist. Optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) may be isomerized during isolation and/or purification from the reaction mixture. Therefore, the diastereo ratio (syn/anti ratio) and enantiomeric excess (ee(%)) of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) are desirably measured without isolation and/or purification after completion of the aldol reaction, but after conversion of 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) to a compound free of isomerization during reaction, isolation and purification. In the present invention, optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) is converted to a corresponding acetal compound (an optically active acetal compound represented by the formula (5):

wherein

-   R¹, R², R³ and R⁸ are as defined above, and -   the carbon atom marked with * is an asymmetric carbon atom), or a     corresponding optically active α,β-unsaturated ester compound (an     optically active α,β-unsaturated ester compound represented by the     formula (6):

wherein

-   R², R³ and R⁹ are as defined above, and -   the carbon atom marked with * is an asymmetric carbon atom).

Optically active acetal compound (5) is produced by a step of reacting the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), or optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, with R⁸OH or HC(OR⁸)₃ wherein R⁸ is as defined above, in the presence of an acid catalyst (acetalization reaction step).

Optically active acetal compound (5) is preferably produced by,

-   (A) a step of reacting optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after     isolation but without purification with R⁸OH wherein R⁸ is as     defined above in the presence of an acid catalyst, or -   (B) a step of reacting the reaction mixture after completion of the     aldol reaction which contains optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) with     HC(OR⁸)₃ wherein R⁸ is as defined above in the presence of an acid     catalyst.

First, step A is explained below.

The amount of R⁸OH to be used is preferably 2-200 mol, more preferably 10-100 mol, per 1 mol of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), in view of yield and economic efficiency. In step A, R⁸OH can also be a reaction solvent.

Examples of the acid catalyst to be used include pyridinium p-toluenesulfonate, and p-toluenesulfonic acid and a hydrate (monohydrate) thereof. Among them, pyridinium p-toluenesulfonate is preferable in view of reaction selectivity.

The amount of the acid catalyst to be used is preferably 0.01-1 mol, more preferably 0.01-0.1 mol, per 1 mol of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), in view of reactive and economic efficiency.

The acetalization reaction is carried out by a method of adding R⁸OH and an acid catalyst to optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, and the mixing them; a method of adding an acid catalyst to optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, and then adding R⁸OH thereto, and mixing them; and the like. In view of convenient operation, a method of adding R⁸OH and an acid catalyst to optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, and mixing them is preferable.

The acetalization reaction is carried out preferably within the range of 0-100° C., more preferably within the range of 20-80° C., particularly preferably within the range of 40-60° C., though depending on the kind of R⁸OH and the acid catalyst.

While the reaction time varies depending on the kind of R⁸OH and the acid catalyst, and the reaction temperature, it is preferably 10 min-50 hr, more preferably 30 min-20 hr, particularly preferably 1-10 hr.

The progress of the reaction can be confirmed by an analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

Next, step B is explained below.

The amount of HC(OR⁸)₃ to be used is preferably 1-20 mol, more preferably 3-10 mol, per 1 mol of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), in view of yield and economic efficiency.

Examples of the acid catalyst to be used include p-toluenesulfonic acid and a hydrate (monohydrate) thereof, and pyridinium p-toluenesulfonate. Among them, p-toluenesulfonic acid and a hydrate (monohydrate) thereof are preferable in view of yield and economic efficiency.

The amount of the acid catalyst to be used is preferably 0.01-1 mol, more preferably 0.01-0.1 mol, per 1 mol of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), in view of reaction rate.

The acetalization reaction is carried out by a method of adding HC(OR⁸)₃ and an acid catalyst to the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), and mixing them; a method of adding an acid catalyst to the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), and then adding HC(OR⁸)₃, and mixing them; and the like. Among them, a method of adding HC(OR⁸)₃ and an acid catalyst to the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), and mixing them is preferable in view of convenient operation.

The acetalization reaction is carried out preferably within the range of 0-100° C., more preferably within the range of 10-40° C., particularly preferably within the range of 20-30° C., though depending on the kind of HC(OR⁸)₃ and the acid to catalyst.

While the reaction time varies depending on the kind of HC(OR⁸)₃ and the acid catalyst, and the reaction temperature, it is preferably 10 min-50 hr, more preferably 30 min-20 hr, particularly preferably 1-10 hr.

The progress of the reaction can be confirmed by an analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

Optically active acetal compound (5) contained in thus obtained reaction mixture can be isolated by subjecting the reaction mixture to a post-treatment using a conventional method (e.g., neutralization, extraction, washing with water, distillation, crystallization etc.), and purified by subjecting optically active acetal compound (5) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment using activated carbon, silica, alumina and the like, or chromatography treatment using silica gel column chromatography and the like.

Optically active α,β-unsaturated ester compound (6) is produced by a step of reacting the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), or optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, with Ph₃P═CHCO₂R⁹ wherein Ph and R⁹ are as defined above (Wittig reaction step).

The amount of Ph₃P═CHCO₂R⁹ to be used is preferably 0.01-5 mol, more preferably 0.5-2 mol, per 1 mol of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), in view of yield and economic efficiency.

When optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification is used, examples of the solvent to be used for the Wittig reaction include an aromatic hydrocarbon solvent (e.g., toluene, benzene, xylene); an alcohol solvent (e.g., methanol, ethanol); a halogenated hydrocarbon solvent (e.g., chloroform, dichloromethane, carbon tetrachloride); an ether solvent (e.g., diethyl ether, tetrahydrofuran); a nitrile solvent (e.g., acetonitrile); an aprotic polar solvent (e.g., dimethylformamide, dimethylacetamide); a mixed solvent thereof and the like. The amount of the solvent to be used is preferably 5-100 mL per 1 g of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4).

The Wittig reaction is carried out by a method of adding Ph₃P═CHCO₂R⁹ to the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), or optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, and mixing them; a method of adding the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), or optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, to Ph₃P═CHCO₂R⁹, and mixing them; and the like. Among them, a method of adding Ph₃P═CHCO₂R⁹ to the reaction mixture after completion of the aldol reaction which contains optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4), or optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) after isolation but without purification, and mixing them is preferable in view of convenient operation.

The Wittig reaction is carried out preferably within the range of 0-100° C., more preferably within the range of 10-40° C., particularly preferably within the range of 20-30° C., though depending on the kind of Ph₃P═CHCO₂R⁹.

While the reaction time varies depending on the kind of Ph₃P═CHCO₂R⁹ and the reaction temperature, it is preferably 10 min-50 hr, more preferably 30 min-20 hr, particularly preferably 1-10 hr.

The progress of the reaction can be confirmed by an analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

Optically active α,β-unsaturated ester compound (6) contained in thus obtained reaction mixture can be isolated by subjecting the reaction mixture to a post-treatment using a conventional method (e.g., neutralization, extraction, washing with water, distillation, crystallization etc.), and purified by subjecting optically active α,β-unsaturated ester compound (6) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment using activated carbon, silica, alumina and the like, or chromatography treatment using silica gel column chromatography and the like.

The diastereo ratio (syn/anti ratio) and enantiomeric excess of the obtained optically active acetal compound (5) or optically active α,β-unsaturated ester compound (6) are measured. The measured diastereo ratio (syn/anti ratio) and enantiomeric excess correspond to those of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4).

When R² and R³ in aldehyde (2) are different groups, in the aldol reaction step of the present invention, the anti-form of optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) is preferentially obtained. The diastereoselectivity showing a diastereo ratio (syn/anti ratio) of, for example, 50/50 or more, or, for example, 20/80 or more, is available.

In the aldol reaction step of the present invention, when optically active pyrrolidine compound (3a) wherein the absolute configuration of C** is S-configuration, i.e., an optically active pyrrolidine compound represented by the formula (3a-S):

-   wherein Ar¹ and Ar² are as defined above, -   is used as a catalyst, optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) wherein     the absolute configuration of C* is R-configuration, i.e., an     optically active 3-substituted-3-formyl-2-hydroxypropanoic acid     compound represented by the formula (4R):

-   wherein R¹, R² and R³ are as defined above, -   is preferentially obtained.

On the other hand, when optically active pyrrolidine compound (3a) wherein the absolute configuration of C** is R-configuration, i.e., an optically active pyrrolidine compound represented by the formula (3a-R):

-   wherein Ar¹ and Ar² are as defined above, -   is used as a catalyst, optically active     3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) wherein     the absolute configuration of C* is S-configuration, i.e., an     optically active 3-substituted-3-formyl-2-hydroxypropanoic acid     compound represented by the formula (4S):

-   wherein R¹, R² and R³ are as defined above, -   is preferentially obtained.

Therefore, in the aldol reaction step in the present invention, the enantioselectivity showing an enantiomeric excess of, for example, 50ee % or more, or, for example, 80ee % or more, is available.

EXAMPLES

The present invention is explained more specifically in the following by referring to Examples.

Ethyl glyoxylate (polymer) (in toluene, 47%; purchased from TCI (Tokyo Chemical Industry Co., Ltd.); catalog number: G0242) was used. All of liquid aldehyde and solvent other than ethyl glyoxylate were distilled prior to use.

All of the reaction was performed under an argon atmosphere, and monitored using thin layer chromatography using Merck 60 F₂₅₄ precoated silica gel plate (0.25 mm thickness). Preparative thin layer chromatography was performed using Wakogel B-5F purchased from Wako Pure Chemical Industries, Ltd. (Japan, Tokyo). Flash chromatography was performed using silica gel 60N manufactured by Kanto Chemical Co., Inc (Japan, Tokyo).

FT-IR spectrum was measured using JASCO FT/IR-410 spectrometer.

¹H and ¹³C-NMR spectrum was measured using Bruker AM400 (400 MHz for ¹H-NMR, 100 MHz for ¹³C-NMR) apparatus. ¹H-NMR data was reported as chemical shift (δppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constant (Hz), integral and assignment. ¹³C-NMR data was reported as a chemical shift.

High resolution mass spectrum analysis (HRMS) was performed using Bruker ESI-TOF MS and APCI-TOF MS.

HPLC analysis was performed using HITACHI Elite LaChrom Series HPLC using CHIRALCEL OB-H (0.46 cm×25 cm), CHIRALPAK IA (0.46 cm×25 cm) and CHIRALPAK IB (0.46 cm×25 cm), while monitoring using UV detection at respective suitable wavelengths.

Example 1-1 and 1-2

To ethyl glyoxylate polymer (108.6 mg, 47% toluene solution, 0.5 mmol) were added an optically active pyrrolidine compound (catalyst a or b, 0.05 mmol) as a catalyst, and propanal (145 mg, 2.5 mmol). The reaction mixture was stirred at 23° C. for 24 hr, and the toluene and excess of propanal were evaporated under reduced pressure. To the residue were added benzene (5 mL) and Ph₃P═CHCO₂Et (348 mg, 1.0 mmol). The reaction mixture was stirred at 23° C. for 24 hr, and filtered through silica gel pad to quench the Wittig reaction, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate:hexane=1:2) to give 1,6-diethyl (4R,5R,E)-5-hydroxy-4-methylhex-2-enedioate. The yield, syn/anti ratio and enantiomeric excess are shown in Table 1. The yield is calculated as a yield in 2 steps. The syn/anti ratio was measured by ¹H-NMR spectrum. The enantiomeric excess was measured by HPLC using CHIRALCEL OB-H column (^(i)PrOH:hexane=1:100, 1 mL/min).

¹H-NMR (CDCl₃, 400 MHz): δ 1.17(3H,d,J=6.8 Hz), 1.20-1.31(6H,m), 2.73-2.84(1H,m), 4.11-4.30(5H,m), 5.81(1H,dd,J=15.6,0.8 Hz), 6.85(1H,dd,J=15.6,0.8 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.1, 15.6, 40.4, 60.3, 61.9, 73.7, 122.6, 147.5, 166.1, 173.4;

IR (neat): ν 3481, 2981, 1719, 1654, 1456, 1370, 1278, 1183, 1029, 865 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₁H₁₈O₅Na]: Calculated 253.1046. Found 253.1058.

[α]_(D) ^(18° C.) +8.7 (c=0.6, CHCl₃);

the retention time of the minor enantiomer=22.8 min, and the retention time of the major enantiomer=31.8 min.

Example 1-3-1-8

The steps were performed in the same manner as in Example 1-1 except that ethyl glyoxylate polymer was concentrated, and to the residue were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (catalyst b, 26.3 mg, 0.05 mmol), propanal (145 mg, 2.5 mmol) and a solvent (0.5 ml) shown in Table 1. The yield, syn/anti ratio and enantiomeric excess are shown in Table 1.

Example 1-9

The steps were performed in the same manner as in Example 1-1 except that ethyl glyoxylate polymer was concentrated, and to the residue were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (catalyst b, 26.3 mg, 0.05 mmol), propanal (145 mg, 2.5 mmol), acetonitrile (0.5 ml, 1 M) and water (27.3 μL, 1.5 mmol). The yield, syn/anti ratio and enantiomeric excess are shown in Table 1.

Example 1-10

The steps were performed in the same manner as in Example 1-1 except that ethyl glyoxylate polymer was concentrated, and to the residue were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (catalyst b, 26.3 mg, 0.05 mmol), propanal (43.5 mg, 0.75 mmol), acetonitrile (0.5 ml, 1 M) and water (27.3 μL, 1.5 mmol). The yield, syn/anti ratio and enantiomeric excess are shown in Table 1.

TABLE 1 yield Example catalyst solvent (%) syn:anti ee % 1-1 a toluene 57 1:4.6 86 1-2 b toluene 59 1:4.3 92 1-3 b MeOH 18 1:4.9 90 1-4 b DMF 41 1:2.0 62 1-5 b CHCl₃ 55 1:3.8 94 1-6 b THF 50 1:3.7 95 1-7 b H₂O 67 1:3.6 92 1-8 b CH₃CN 73 1:4.4 98 1-9 b aq•CH₃CN 86 1:4.1 96 1-10 b aq•CH₃CN 93 1:9.8 98

Example 2-1-2-4

To ethyl glyoxylate polymer obtained by concentrating 47% toluene solution (108.6 mg, 0.5 mmol) were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine in an amount shown in Table 2 (the amount relative to ethyl glyoxylate (in monomer amount)), propanal (43.5 mg, 0.75 mmol), acetonitrile (0.5 ml, 1 M) and water (27.3 μL, 1.5 mmol). The reaction mixture was stirred at 23° C. for 24 hr, and Ph₃P═CHCO₂Et (348 mg, 1.0 mmol) was added thereto. The reaction mixture was stirred at 23° C. for 24 hr, and filtered through silica gel pad to quench the Wittig reaction, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate:hexane=1:2) to give 1,6-diethyl (4R,5R,E)-5-hydroxy-4-methylhex-2-enedioate. The yield, syn/anti ratio and enantiomeric excess are shown in Table 2. The yield is calculated as a yield in 2 steps. The syn/anti ratio was measured by ¹H-NMR spectrum. The enantiomeric excess was measured by HPLC using CHIRALCEL OB-H column (^(i)PrOH:hexane=1:100, 1 mL/min).

TABLE 2 catalyst time yield Example (mol %) (h) (%) syn:anti ee (%) 2-1 10 20 93 1:9.8 98 2-2 5 30 quant. 1:7.6 98 2-3 2 40 quant. 1:7.3 99 2-4 1 48 61 1:11.5 99

Example 3-1-3-6

To ethyl glyoxylate polymer obtained by concentrating 47% toluene solution (108.6 mg, 0.5 mmol) were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (26.3 mg, 0.05 mmol), acetonitrile (0.5 mL, 1.0 M), water (27.3 μL, 1.5 mmol) and the corresponding aldehyde (0.75 mmol). The reaction mixture was stirred at 23° C. for 24 hr, and Ph₃P═CHCO₂Et (348 mg, 1.0 mmol) was added thereto. The reaction mixture was stirred at 23° C. for 24 hr, and filtered through silica gel pad to quench the Wittig reaction, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate:hexane=1:2) to give the corresponding α,β-unsaturated ester. The yield, syn/anti ratio and enantiomeric excess are shown in Table 3. The yield is calculated as a yield in 2 steps. The syn/anti ratio was measured by ¹H-NMR spectrum.

1-tert-butyl 6-ethyl (R,E)-5-hydroxy-hex-2-enedioate Example 3-1

¹H-NMR (CDCl₃, 400 MHz): δ 1.27(3H,t,J=7.2 Hz), 1.29(9H,s), 2.46-2.56(1H,m), 2.60-2.70(1H,m), 3.02(1H,br-s), 4.18-4.30(3H,m), 5.82(1H,d,J=15.6 Hz), 6.79(1H,dt,J=15.6,7.2 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.1, 28.0, 36.8, 61.9, 69.3, 80.3, 126.3, 141.3, 165.3, 173.9;

IR (neat): ν 3481, 2980, 2936, 1715, 1655, 1369, 1153, 1106, 1027, 981, 850 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₂H₂₀O₅Na]: Calculated 267.1203. Found 267.1204.

[α]_(D) ^(17° C.) +10.0 (c=1.9, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALCEL OB-H column (^(i)PrOH:hexane=1:10, 1 mL/min) (the retention time of the minor enantiomer=9.9 min, and the retention time of the major enantiomer=13.8 min).

1,6-diethyl (4R,5R,E)-5-hydroxy-4-methylhex-2-enedioate Example 3-2

¹H-NMR (CDCl₃, 400 MHz): δ 1.17(3H,d,J=6.8 Hz), 1.20-1.31(6H,m), 2.73-2.84(1H,m), 4.11-4.30(5H,m), 5.81(1H,dd,J=15.6,0.8 Hz), 6.85(1H,dd,J=15.6,0.8 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.1, 15.6, 40.4, 60.3, 61.9, 73.7, 122.6, 147.5, 166.1, 173.4;

IR (neat): ν 3481, 2981, 1719, 1654, 1456, 1370, 1278, 1183, 1029, 865 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₁H₁₈O₅Na]: Calculated 253.1046. Found 253.1058.

[α]_(D) ^(18° C.) +8.7 (0.6, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALCEL OB-H column (^(i)PrOH:hexane=1:100, 1 mL/min) (the retention time of the minor enantiomer=22.8 min, and the retention time of the major enantiomer=31.8 min).

1-tert-butyl 6-ethyl (4R,5R,E)-5-hydroxy-4-ethylhex-2-enedioate Example 3-3

¹H-NMR (CDCl₃, 400 MHz): δ 0.92(3H,t,J=7.6 Hz), 1.28(3H,t,J=6.8 Hz), 1.45(9H,s), 1.50-1.75(4H,m), 2.47(1H,tq,J=2.8,9.2 Hz), 2.80(1H,br-s), 4.16-4.32(3H,m), 5.72(1H,dd,J=0.8,15.6 Hz), 6.66(1H,dd,J=9.2,15.6 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 11.7, 14.1, 23.4, 28.0, 47.7, 61.7, 72.3, 80.1, 125.5, 145.0, 165.2, 173.7;

IR (neat): ν 3488, 2979, 2935, 1729, 1724, 1654, 1368, 1157, 1026, 982 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₄H₂₄O₅Na]: Calculated 295.1516. Found: 95.1519.

[α]_(D) ^(18° C.) −14.8 (c=1.1, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IA column (^(i)PrOH:hexane=1:30, 1 mL/min) (the retention time of the minor enantiomer=15.1 min, and the retention time of the major enantiomer=12.3 min).

1-tert-butyl 6-ethyl (4R,5R,E)-5-hydroxy-4-normal-propylhex-2-enedioate Example 3-4

¹H-NMR (CDCl₃, 400 MHz): δ 0.91(3H,t,J=7.2 Hz), 1.29(3H,t,J=6.8 Hz), 1.29-1.38(1H,m), 1.46(9H,s), 1.48-1.66 (4H,m), 2.59(1H,ddt,J=2.8,5.6,8.8 Hz), 4.18-4.32(3H,m), 5.72(1H,d,J=16.0 Hz), 6.67(1H,dd,J=9.6,16.0 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 13.9, 14.2, 20.3, 28.1, 32.6, 45.8, 61.9, 72.7, 80.3, 125.5, 145.2, 165.3, 173.8;

R(neat): ν 3470, 2961, 2931, 1733, 1716, 1454, 1368, 1250, 1158, 1139 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₅H₂₆O₅Na]: Calculated 309.1672. Found: 306.1678.

[α]_(D) ^(19° C.) −14.6 (c=2.2, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IA column (^(i)PrOH:hexane=1:100, 1 mL/min) after 2,4-dinitrobenzoylation of the Wittig resultant product (the retention time of the minor enantiomer=50.6 min, and the retention time of the major enantiomer=31.0 min).

1-tert-butyl 6-ethyl (4R,5R,E)-5-hydroxy-4-iso-propylhex-2-enedioate Example 3-5

¹H-NMR (CDCl₃, 400 MHz): δ 0.90(3H,d,J=6.8 Hz), 1.06(3H,d,J=6.4 Hz), 1.28(3H,t,J=7.2 Hz), 1.46(9H,s), 1.97(1H,dq,J=9.2,6.8 Hz), 2.20(1H,dt,J=2.4,9.6 Hz), 2.78(1H,br-s), 4.20(1H,dq,J=7.2,10.4 Hz), 4.27(1H,dq,J=7.2,10.4 Hz), 4.40(1H,br-s), 5.69(1H,d,J=15.6 Hz), 6.70(1H,dd,J=10.4,15.6 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.0, 20.2, 20.9, 27.9, 28.0, 52.8, 61.7, 70.8, 80.1, 125.9, 144.4, 164.9, 174.0;

IR (neat): ν 3442, 2974, 2931, 1733, 1716, 1366, 1282, 1246, 1157, 1143 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₅H₂₆C₅Na]: Calculated 309.1672. Found 309.1683.

[α]_(D) ^(20° C.) −27.4 (c=0.87, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IA column (^(i)PrOH:hexane=1:100, 1 mL/min) after 2,4-dinitrobenzoylation of the Wittig resultant product (the retention time of the minor enantiomer=33.9 min, and the retention time of the major enantiomer=26.3 min).

1-tert-butyl 6-ethyl (4S,5R,E)-5-hydroxy-4-benzylhex-2-enedioate Example 3-6

¹H-NMR (CDCl₃, 400 MHz): δ 1.25(3H,t,J=7.2 Hz), 1.45(9H,s), 2.76-2.90 (2H, m), 2.96 (1H, dd, J=8.4, 12.4 Hz), 4.09 (1H, dd, J=2.0, 4.4 Hz), 4.16(1H,dq,J=7.2,10.8 Hz), 4.25(1H,dq,J=7.2,10.8 Hz), 5.72(1H,d,J=15.6 Hz), 6.76(1H,dq,J=6.8,15.6 Hz), 7.32-7.22(5H,m);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.2, 28.1, 36.8, 47.4, 61.9, 70.8, 80.3, 125.7, 126.4, 128.5, 129.3, 138.6, 144.2, 165.1, 173.9;

IR (neat): ν 3500, 2979, 1714, 1652, 1456, 1368, 1319, 1253, 1149, 1110, 985 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₉H₂₆O₅Na]: Calculated 356.1672. Found 357.1668.

[α]_(D) ^(20° C.) −47.2 (c=0.63, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IB column (^(i)PrOH:hexane=1:100, 1 mL/min) after benzoylation of the Wittig resultant product (the retention time of the minor enantiomer=17.9 min, and the retention time of the major enantiomer=15.6 min).

Example 3-7-3-8

In the same manner as in Example 3-1 except that to ethyl glyoxylate polymer obtained by concentrating 47% toluene solution (162.9 mg, 0.75 mmol) were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (26.3 mg, 0.05 mmol), acetonitrile (0.25 mL, 0.5 M), water (27.3 μL, 1.5 mmol) and the corresponding aldehyde (0.5 mmol), the reaction mixture was stirred at 5° C. for 38 hr, and Ph₃P═CHCO₂Et (348 mg, 1.0 mmol) was added thereto, the corresponding α,β-unsaturated ester was obtained. The yield, syn/anti ratio and enantiomeric excess are shown in Table 3, in which the yield in 2 steps is calculated. The syn/anti ratio was measured by ¹H-NMR spectrum.

1,6-diethyl (4S,5R,E)-5-hydroxy-4-(p-methoxybenzoylmethyl)hex-2-enedioate Example 3-8

¹H-NMR (CDCl₃, 400 MHz): δ 1.27(3H,dt,J=3.2,7.2 Hz), 2.95-3.03(2H,m), 3.55(1H,dd,J=5.6,9.2 Hz), 3.68(1H,t,J=8.8 Hz), 3.81(3H,s), 4.17(2H,q,J=7.2 Hz), 4.18-4.26(2H,m), 4.43-4.52(2H,m), 5.87(1H,dd,J=0.8,15.6 Hz), 6.80(1H,dd,J=9.2,15.6 Hz), 6.88(2H,br-d,J=8.8 Hz), 7.25(2H,br-d,J=8.8 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.2, 46.0, 55.3, 60.4, 62.0, 68.9, 70.1, 73.1, 113.8, 124.9, 129.4, 129.9, 142.8, 159.3, 165.8, 173.7;

IR (neat): ν 3533, 2983, 2837, 1740, 1724, 1613, 1514, 1466, 1368, 1177, 1033, 820 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₉H₂₆C₇Na]: Calculated 389.1571. Found 389.1580.

[α]_(D) ^(19° C.) −5.3 (c=0.70, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IC column (^(i)PrOH:hexane=1:10, 1 mL/min) after benzoylation of the Wittig resultant product (the retention time of the minor enantiomer=17.6 min, and the retention time of the major enantiomer=23.8 min).

Example 3-9-3-11

The reaction was carried out by the following Method A or Method B.

Method A

To ethyl glyoxylate polymer obtained by concentrating 47% toluene solution (108.6 mg, 0.5 mmol) were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (26.3 mg, 0.05 mmol), acetonitrile (0.5 mL, 1.0 M), water (27.3 μL, 1.5 mmol) and the corresponding aldehyde (0.75 mmol). The reaction mixture was stirred at 23° C. for 48 hr, and the solvent and excess aldehyde were evaporated under reduced pressure. To the residue were added methanol (1.0 ml, 24.7 mmol) and pyridinium p-toluenesulfonate (12.6 mg, 0.05 mmol), and the reaction mixture was stirred at 50° C. for 5 hr, and quenched with saturated aqueous sodium hydrogen carbonate solution. The organic substance was extracted with chloroform three times, and the extract was dried over anhydrous Na₂SO₄, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane=1:10) to give an acetal resultant product. The yield, syn/anti ratio and enantiomeric excess are shown in Table 3, in which the yield in 2 steps is calculated. The syn/anti ratio was measured by ¹H-NMR spectrum. The enantiomeric excess was measured by HPLC with chiral column after conversion to the corresponding 2,4-dinitrobenzoate.

Method B

To ethyl glyoxylate polymer obtained by concentrating 47% toluene solution (108.6 mg, 0.5 mmol) were added (S)-2-[bis(3,5-bis(trifluoromethyl)phenyl)hydroxymethyl]pyrrolidine (26.3 mg, 0.05 mmol), acetonitrile (0.5 mL, 1.0 M), water (27.3 μL, 1.5 mmol) and the corresponding aldehyde (0.75 mmol). The reaction mixture was stirred at 23° C. for 48 hr, and trimethyl orthoformate (274 μL, 2.5 mmol) and p-toluenesulfonic acid monohydrate (9.5 mg, 0.05 mmol) were added thereto. The reaction was quenched with saturated aqueous sodium hydrogen carbonate solution. The organic substance was extracted with chloroform three times, and the extract was dried over anhydrous Na₂SO₄, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane=1:10) to give an acetal resultant product. The yield, syn/anti ratio and enantiomeric excess are shown in Table 3, in which the yield in 2 steps is calculated. The syn/anti ratio was measured by ¹H-NMR spectrum. The enantiomeric excess was measured by HPLC with chiral column after conversion to the corresponding 2,4-dinitrobenzoate.

ethyl (2R,3S)-2-hydroxy-4,4-dimethoxy-3-methylbutanoate Example 3-9

¹H-NMR (CDCl₃, 400 MHz): δ 1.05(3H,d,J=7.6 Hz), 1.28(3H,t,J=7.2 Hz), 3.12(1H,s), 2.32(1H,d of quint.,J=3.2,7.2 Hz), 3.31(3H,s), 3.32(3H,s), 4.21(1H,q,J=7.2 Hz), 4.30(1H,d,J=7.6 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 12.7, 14.1, 39.7, 53.0, 55.7, 61.4, 72.7, 106.0, 174.4;

IR (neat): ν 3501, 2982, 2939, 1733, 1464, 1256, 1226, 1131, 1059, 955 cm⁻¹;

HRMS (ESI): [M+Na] [C₉H₁₈O₅Na]: Calculated 229.1046. Found 229.1054.

[α]_(D) ^(17° C.) −17.0 (c=1.0, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IA column (^(i)PrOH:hexane=1:50, 1 mL/min) (the retention time of the minor enantiomer=22.9 min, and the retention time of the major enantiomer=20.3 min).

ethyl (2R,3S)-3-benzyloxy-4,4-dimethoxy-2-hydroxybutanoate Example 3-10

¹H-NMR (CDCl₃, 400 MHz): δ 1.28(3H,t,J=6.8 Hz), 3.08(1H,d,J=5.2 Hz), 3.40(3H,s), 3.45(3H,s), 3.80(1H,dd,J=2.4,7.2 Hz), 4.23(2H,q,J=7.2 Hz), 4.41(1H,dd,J=2.4,4.8 Hz), 4.54(1H,d,J=7.2 Hz), 4.71(1H,d,J=12.0 Hz), 4.77(1H,d,J=12.0 Hz), 7.26-7.40(5H, m);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.1, 55.6, 56.1, 61.7, 71.2, 73.6, 80.8, 105.0, 127.7, 127.9, 128.4, 138.1, 172.2;

IR (neat): ν 3522, 3438, 2986, 2834, 1742, 1455, 1200, 1138, 1069, 1027, 745, 699 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₅H₂₂C₆Na]: Calculated 321.1309. Found 321.1309.

[α]_(D) ^(20° C.) −31.5 (c=0.90, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IB column (^(i)PrOH:hexane=1:20, 1 mL/min) (the retention time of the minor enantiomer=20.7 min, and the retention time of the major enantiomer=26.2 min).

ethyl 3-phthalimidyl-4,4-dimethoxy-2-hydroxybutanoate Example 3-11 Minor Diastereomer

¹H-NMR (CDCl₃, 400 MHz): δ 1.17(3H,t,J=7.2 Hz), 3.26(3H,s), 3.55(3H,s), 4.07(1H,dq,J=10.8,7.2 Hz), 4.20(1H,br-d,J=10.8 Hz), 4.68-4.77(2H,m), 5.24(1H,d,J=8.4 Hz), 7.74(2H,dd,J=3.2,5.6 Hz), 7.85(2H,dd,J=3.2,5.6 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.0, 53.0, 54.8, 55.9, 61.6, 70.9, 99.6, 123.7, 131.5, 134.4, 168.7, 172.1;

IR (neat): ν 3472, 2941, 1775, 1747, 1715, 1389, 1207, 1123, 1069, 772 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₆H₁₉NO₇Na]: Calculated 360.1054. Found: 360.1063.

[α]_(D) ^(21° C.) +25.8 (c=1.34, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IB column (^(i)PrOH:hexane=1:30, 1 mL/min) (the retention time of the minor enantiomer=21.9 min, and the retention time of the major enantiomer=19.4 min).

ethyl 3-phthalimidyl-4,4-dimethoxy-2-hydroxybutanoate Example 3-11 Major Diastereomer

¹H-NMR (CDCl₃, 400 MHz): δ 1.32(3H,t,J=7.2 Hz), 3.27(3H,s), 3.49(3H,s), 3.67(1H,br-d,J=3.6 Hz), 4.29(2H,dq,J=2.4,7.2 Hz), 4.55(1H,br-t,J=3.6 Hz), 4.81(1H,dd,J=3.6,8.8 Hz), 5.42(1H,d,J=8.8 Hz), 7.73(2H,dd,J=3.2,5.2 Hz), 7.85(2H,dd,J=3.2,5.2 Hz);

¹³C-NMR (CDCl₃, 100 MHz): δ 14.0, 52.8, 54.7, 56.0, 62.1, 70.6, 99.7, 123.5, 131.7, 134.2, 168.2, 171.6;

IR (neat): ν 3478, 2941, 2838, 1776, 1716, 1469, 1388, 1216, 1109, 1071, 722 cm⁻¹;

HRMS (ESI): [M+Na] [C₁₆H₁₉NO₇Na]: Calculated 360.1054. Found 360.106.

[α]_(D) ^(21° C.) −33.5 (c=0.52, CHCl₃);

The enantiomeric excess was measured by HPLC using CHIRALPAK IB column (^(i)PrOH:hexane=1:30, 1 mL/min) (the retention time of the minor enantiomer=35.3 min, and the retention time of the major enantiomer=30.7 min).

TABLE 3 Exam- yield syn: ee ple resultant product (%) anti (%) 3-1 

74 —  90 3-2 

93 1:9.8   98 3-3 

quant. 1:16   92 3-4 

89 1:19   96 3-5 

quant. 1:19   97 3-6 

92 1:>20 >99 3-7 

78 1:>20  97 3-8 

95 1:6.8   99 3-9 

74 1:9.7   99 3-10

78 1:>20  98 3-11

88 1:1.4  91, 91

INDUSTRIAL APPLICABILITY

According to the production method of the present invention, since the reactivity of the reaction in the presence of optically active pyrrolidine compound (3) as a catalyst is superior even when glyoxylic acid compound (1-1) or (1-2) is used in the form of a polymer, a commercially available product can be used, and a complicated step such as thermal decomposition and distillation immediately before use is not necessary. In addition, reaction under aqueous conditions is also possible. Furthermore, when reacted in toluene, a commercially available product can be advantageously used directly without evaporating toluene.

Using optically active pyrrolidine compound (3) having a particular structure and a particular solvent, an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound (4) can be produced in a high yield with superior enantioselectivity and diastereoselectivity (when R² and R³ in aldehyde (2) are different groups). 

The invention claimed is:
 1. A method of producing an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound of formula (4):

wherein R¹ is (i) a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from the following Group G1 or (ii) a hydrogen atom, R² and R³ are each independently (i) a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from the following Group G1, (ii) a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from the following Group G1, (iii) a heterocyclic group optionally having substituent(s) selected from the following Group G1 or (iv) a hydrogen atom, and the carbon atom marked with * is an asymmetric carbon atom, which comprises a step of reacting a glyoxylic acid compound of formula (1-1):

wherein R¹ is as defined above, and n is an integer of 2 or more, or a glyoxylic acid compound of formula (1-2):

wherein R¹ and n are as defined above, with an aldehyde of formula (2):

wherein R² and R³ are as defined above, in the presence of an optically active pyrrolidine compound of formula (3):

wherein Ar¹ and Ar² are each independently (i) a phenyl group optionally having substituent(s) selected from the following Group G2, (ii) a C₁-C₁₂ chain hydrocarbon group, (iii) a C₃-C₁₂ alicyclic hydrocarbon group or (iv) a hydrogen atom, R⁴ is (i) a hydrogen atom, (ii) a fluorine atom, (iii) a hydroxyl group, (iv) a C₁-C₁₂ alkoxy group, (v) a C₁-C₁₂ fluorinated alkyloxy group or (vi) a silyloxy group reprsented by —OSiR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are each independently (i) a C₁-C₈ alkyl group or (ii) a C₆-C₂₀ aryl group, and the carbon atom marked with ** is an asymmetric carbon atom; Group G1 is (i) a C₆-C₂₀ aryl group optionally having substituent(s) selected from Group G2, (ii) an aromatic heterocyclic group optionally having substituent(s) selected from Group G2, (iii) a C₁-C₁₂ alkoxy group, (iv) a C₁-C₁₂ alkoxy group having C₆-C₂₀ aryl group(s) optionally having substituent(s) selected from Group G2, (v) a halogen atom, or (vi) an oxo group; Group G2 is (i) a C₁-C₁₂ alkyl group, (ii) a C₁-C₁₂ alkoxy group, (iii) a C₂-C₁₃ alkoxycarbonyl group, (iv) a C₁-C₁₂ fluorinated alkyl group, (v) a C₂-C₁₃ acyl group, (vi) a nitro group, (vii) a cyano group, (viii) a protected amino group, or (ix) a halogen atom.
 2. The method of claim 1, wherein the reaction is carried out in the presence of a solvent.
 3. The method of claim 2, wherein the solvent is at least one selected from the group consisting of an aromatic hydrocarbon solvent, an alcohol solvent, a halogenated hydrocarbon solvent, an ether solvent, a nitrile solvent and water.
 4. The method of claim 1, wherein the reaction is carried out within the range of 0-50° C.
 5. The method of claim 1, wherein R³ is a hydrogen atom.
 6. The method of claim 1, wherein R⁴ is a hydroxyl group, and Ar¹ and Ar² are each independently a phenyl group optionally having C₁-C₁₂ fluorinated alkyl group(s).
 7. The method of claim 1, wherein R⁴ is a hydroxyl group, and Ar¹ and Ar² are both 3,5-bis(trifluoromethyl)phenyl groups.
 8. The method of claim 6, wherein the absolute configuration of C** is S-configuration, and the absolute configuration of C* is R-configuration.
 9. A method of producing an optically active acetal compound of formula (5):

wherein R¹, R² and R³ are as defined in claim 1, R⁸ is a C₁-C₈ alkyl group, and the carbon atom marked with * is an asymmetric carbon atom, which comprises a step of reacting an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound of formula (4), which is obtained according to the method of claim 1, with R⁸OH or HC(OR⁸)₃ wherein R⁸ is as defined above, in the presence of an acid catalyst.
 10. A method of producing an optically active α,β-unsaturated ester compound of formula (6):

wherein R¹, R² and R³ are as defined in claim 1, R⁹ is a C₁-C₈ alkyl group, and the carbon atom marked with * is an asymmetric carbon atom, which comprises a step of reacting an optically active 3-substituted-3-formyl-2-hydroxypropanoic acid compound of formula (4), which is obtained according to the method of claim 1, with Ph₃P═CHCO₂R⁹ wherein Ph is a phenyl group, and R⁹ is as defined above.
 11. The method of claim 7, wherein the absolute configuration of C** is S-configuration, and the absolute configuration of C* is R-configuration. 